Bottom Line:
We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population.A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534).Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.

ABSTRACTBloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.

Mentions:
We previously identified deleterious BLM mutations, a splice site mutation (c.3558 + 1G > T) and a nonsense mutation (c.2695C > T; p.Arg899*), in two individuals that were diagnosed with colorectal cancer at the age of 29 and 37 years, respectively (Fig. 1a and Table 1; deVoer et al. unpublished data). Both mutations were reported in the Bloom’s syndrome registry, and are thus found in Bloom’s syndrome patients9. Since there are no precise numbers on the frequency of pathogenic BLM mutations in the general population, we queried the data browser from the Exome Aggregation Consortium (ExAC; n = 61,486)10, a publically available dataset containing exomes from individuals of European, African or Asian ancestry. We established an overall prevalence of known deleterious BLM mutations of approximately one in 900 individuals (0.11%), suggesting that the prevalence of BLM mutations is enriched in our cohort of 55 early-onset CRC patients. To determine whether we could validate these findings, we managed to collect and analyse a cohort of 185 CRC patients diagnosed with CRC before the age of 50 years originating from the Netherlands (n = 105) and Germany (n = 80), as well as a control cohort of 532 healthy individuals, for the presence of deleterious BLM mutations.

Mentions:
We previously identified deleterious BLM mutations, a splice site mutation (c.3558 + 1G > T) and a nonsense mutation (c.2695C > T; p.Arg899*), in two individuals that were diagnosed with colorectal cancer at the age of 29 and 37 years, respectively (Fig. 1a and Table 1; deVoer et al. unpublished data). Both mutations were reported in the Bloom’s syndrome registry, and are thus found in Bloom’s syndrome patients9. Since there are no precise numbers on the frequency of pathogenic BLM mutations in the general population, we queried the data browser from the Exome Aggregation Consortium (ExAC; n = 61,486)10, a publically available dataset containing exomes from individuals of European, African or Asian ancestry. We established an overall prevalence of known deleterious BLM mutations of approximately one in 900 individuals (0.11%), suggesting that the prevalence of BLM mutations is enriched in our cohort of 55 early-onset CRC patients. To determine whether we could validate these findings, we managed to collect and analyse a cohort of 185 CRC patients diagnosed with CRC before the age of 50 years originating from the Netherlands (n = 105) and Germany (n = 80), as well as a control cohort of 532 healthy individuals, for the presence of deleterious BLM mutations.

Bottom Line:
We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population.A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534).Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.

ABSTRACTBloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.